European Union's Horizon Research Articles

Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions

SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n=85) compared with controls (1.1%, n=5) (p<0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of+18 repeats per generation (r2=0.44; p<0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2=0.63; p<0.0001)), resulting in the transmission bias observed in SCA27B pedigrees. SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling. This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

(Invited) Negative Ions, Nanoparticles and Their Transport to Substrates: Towards Better Control of Plasma-Based Fabrication of Surfaces with Tunable Wetting Properties

The removal of pollutants from water, such as oil residues, requires the production of materials with controlled surface properties, especially in terms of their specific surface area and wetting properties [1]. Environmentally friendly processes based on plasma techniques enable the production of surfaces with a wide variety of different properties in terms of their surface topography and chemical composition. An important component that often forms in low-temperature plasmas operated with organic monomers are nanoparticles. Although often considered an undesirable side effect in many applications, nanoparticles can also be used to create nanocomposites or to decorate surfaces to control their wetting properties and their surface roughness [2]. In order to harness the nanoparticles from a plasma it is therefore an essential task to control their formation and ultimately their transport to the reactor walls or to potential substrates. This contribution will focus on the formation of nanoparticles in low temperature, low pressure plasmas operated with different organic monomers as a precursor gas. Although the exact mechanism responsible for the creation of nanoparticles clearly depends on the nature of the process, it is believed that negative ions play a crucial role in the initial stages of the nucleation [3]. In contrast to neutral radicals or positive ions, which are rapidly lost due to diffusion to the reactor walls the residence time of negative ions in the plasma bulk is usually much larger. Negative ions can therefore more easily form larger molecules, which can serve as the basis for the formation of primary clusters in the nanometer or subnanometer range and in this way trigger the agglomeration processes that lead to the formation of larger particles. Since negative ions can leave the plasma during the plasma-off phase of a pulsed discharge, pulsing the plasma is a suitable means to control the accumulation of negative ions and thus the formation of nanoclusters. The experimental results show a complex interplay between pulse frequency or duty cycle and nanoparticle formation. Even the smallest changes in plasma off-time can lead either to a discharge regime that favors nanoparticle formation or to a discharge regime that prevents nanoparticle formation. The minimum plasma off time required to prevent the build- up of particles in a pulsed discharge depends strongly on parameters like power, pressure, gas mixture ratio and the plasma on time. Although the formation of nanoparticles can be very precisely controlled by an appropriate choice of pulse frequency and duty cycle, their transport and controlled deposition on substrates remains a difficult task. In this context, the use of new structured "filtering" electrodes [4] is discussed. The results show that these electrodes allow the deposition of materials with very different surface topographies. Depending on the plasma conditions and the DC voltages applied to parts of the electrodes, the resulting deposits can range from highly localized polymer structures to dense layers of nanoparticles or polymer films with Turing-like patterns. Literature [1] M. Padaki, R. Surya Murali , M.S. Abdullah, N. Misdan , A. Moslehyani , M.A. Kassim , N. Hilal , A.F. Ismail , Desalination, 357,P. 197 (2015)[2] Berndt, J., Acid, H., Kovacevic, E., Boufendi, L., Journal of Applied Physics, 113(6), p.063302. (2013)[3] Berndt, J., Kovacevic, E., Boufendi,L. Journal of Applied Physics, 106, 063309 (2009)[4] Sciacqua, D., Pattyn, C., Jagodar, A., von Wahl, E., Lecas, T., Strunskus, T., Kovacevic, E. and Berndt, J., 2020.. Scientific Reports, 10(1), pp.1-8. Acknowledgement Authors acknowledge the project PEGASUS (Plasma Enabled and Graphene Allowed Synthesis of Unique nano- Structures), funded by the European Union's Horizon research and innovation programme under grant agreement No 766894 and the EU Graphene Flagship FLAG-ERA III JTC 2021 project VEGA (PR-11938). TS, CB ,and JB want to thank HZB for the allocation of synchrotron radiation beamtime at Bessy II. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 730872 (Nr. 18207084-ST and 18207393- ST). TV, CB and JB acknowledge also support obtained via ARD MATEX Region Centre and Erasmus + Program with WHS Recklinghausen and Prof dr Franziska Traeger.

Quantifying Sheet Resistance and in-Plane Electrical Resistivity of PEM Water Electrolyzer Components

PEM water electrolysis is a promising technology for renewable hydrogen production. However, improving the performance and efficiency of PEM water electrolyzers requires a thorough understanding of the properties and behavior of their components. Here we present a robust and effective method for determining the sheet resistance of porous electrodes commonly used in technologies such as PEM water electrolyzers. For this, a new analysis method was developed that relies on industrial printed circuit boards, allowing resistance measurements at ten different length scales ranging from 250 µm to 2500 µm and a 1D mapping of the resistance at each length scale. The sheet resistance of a commercially available reference material is characterized in order to validate the method, and the impact of compression force on the probe-sample contact is demonstrated. Furthermore, the sheet resistance of commonly used PEM water electrolyzer components is investigated. This includes the discussion of the gas diffusion layer, porous transport layer, and catalyst layers coated onto a membrane. Besides, by using an image processing-based method, the thickness distribution of the catalyst layers can be obtained and is correlated with the electrical in-plane resistivity. The results indicate that the sheet resistance is a more relevant parameter than the in-plane electrical resistivity to characterize catalyst layers. We will present a ranking of different PEM water electrolyzer components according to their sheet resistance for both anode and cathode catalyst layers. Acknowledgement This project has received funding from the European Union's Horizon 2020 research and innovation programme under the PROMET-H2 grant agreement No 862253.

(Invited) Structure-Reactivity Relationship for Pt-Rare Earth Electrocatalysts for Oxygen Reduction Reaction

Alloys of Pt with rare-earth metals (REM) have been demonstrated as one of the most promising candidates with high activity towards oxygen reduction reaction and durability with respect to pure Pt and Pt-alloys with late transition metals1,2. However, due to very low reduction potentials and high oxygen affinity of such elements, the synthesis of Pt-REM nanoalloys by conventional chemical methods is not trivial.Our group prepared and characterized a series of carbon supported Pt-REM nanocatalysts using a solid-state route3. A systematic investigation of the influence of the type of rare earth metal (Y, Gd, Nd), of the Pt:REM ratio4, and of the post-synthesis treatment5, on the structural, morphological and electrochemical properties of the prepared electrocatalysts was performed. Operando techniques were used to investigate the evolution of the nanoalloys during the electrochemical experiments, providing evidence for the structural transitions and strain dynamics that govern the electrocatalytic activity towards the ORR. For instance, the evolution of the structural, morphological and compositional properties of Pt-Nd nanoalloys occurring during electrochemical activation was studied by online ICP-MS6.In this presentation an overview of the results obtained on these carbon-supported Pt-REM nanostructured electrocatalysts will be given and the challenges for their application at the PEMFC cathode presented. J. Greeley et al., Nat. Chem., 1, 552–6 (2009).C. A. Campos-Roldán, D. J. Jones, J. Rozière, and S. Cavaliere, ChemCatChem, 14 (2022)Y. Hu, J. O. Jensen, L. N. Cleemann, B. A. Brandes, and Q. Li, J. Am. Chem. Soc., 142, 953–961 (2020)C. A. Campos-Roldán et al., ACS Catal., 11, 13519–13529 (2021).C. A. Campos-Roldán et al., Nanoscale Adv., 4, 26–29 (2022)C. A. Campos-Roldán et al., sumbitted. The research leading to these results has received funding from the IMMORTAL project, which receives funding from the Fuel Cells and Hydrogen 2 Joint Undertaking (now Clean Hydrogen Partnership) under Grant Agreement No. 101006641. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme, Hydrogen Europe and Hydrogen Europe Research.

Load Profile Test Development and Analysis from Heavy Duty Truck Drive Cycles

On their way to their commercialisation, Fuel Cell Heavy Duty Trucks stakeholders need to demonstrate their cost effectiveness against conventional Diesel Trucks. Beyond the economies of scale of all relevant components that are employed in a Fuel Cell Electric Heavy Duty Truck, the durability of the Fuel Cell System and notably that of the Fuel Cell Stack plays an important role in the determination of a competitive cost of ownership.A key factor for durability improvement is the understanding of the degradation mechanisms and their mitigation. Degradation, however, can be very application specific, that is, different degradation mechanisms may be prevalent in heavy duty truck applications compared to passenger cars or stationary use. This is well known to research and industry.The European research project IMMORTAL is exactly aiming at exploring these mechanisms and their mitigation specifically for heavy duty truck application and developing and MEA that meets heavy duty requirements. Within this context, FPT Industrial, a brand of the Iveco Group, assists in defining the specific conditions met by Fuel Cell Stacks used in such powertrains.This presentation discusses how heavy duty truck load profiles can be extracted, how they may differ and how they may be assessed before they are used to define load profile tests (LPTs). It is also discussed how the results of such testing can be used to estimate degradation trends of the Fuel Cell and subsequently its durability and the cost of ownership of fuel cell trucks. The research leading to these results has received funding from the IMMORTAL project, which receives funding from the Fuel Cells and Hydrogen 2 Joint Undertaking (now Clean Hydrogen Partnership) under Grant Agreement No. 101006641. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme, Hydrogen Europe and Hydrogen Europe Research.

Chemical and Electrochemical Interaction of Halide and Sulfide-Based Electrolytes in Solid-State Batteries

Introduction Conventional lithium-ion batteries (LIBs) have found widespread small and large applications. However, safety issues and capacity degradation of the cells, in general, can occur due to the use of toxic and flammable liquid electrolytes [1]. As one of the next-generation LIBs, solid-state lithium batteries (SSBs) have the potential to replace liquid electrolyte LIBs due to their safety and potentially high energy density [2]. The key component of SSBs is the solid-state electrolyte (SSE). Sulfide and halide-based solid electrolytes are among the hot topics in solid electrolyte research for SSBs. Despite the advantages of solid electrolytes, such as good compatibility with high-voltage cathode materials and soft fabrication. However, the poor chemical and electrochemical stability of sulfide and halide-based solid electrolytes towards Li metal has a critical problem that causes the degradation of the lithium/solid electrolyte interface due to the formation of side reaction components that leads to inhibiting lithium kinetics [3]. Results and Discussion Here, we have shown that a combination of halide and argyrodite (Li6PS5Cl) solid electrolytes can lead to the prevention of the formation of unfavorable interactions between solid electrolytes and lithium metal anode. The combination of halide and argyrodite (Li6PS5Cl) in the Li/Li symmetric cell can stabilize cycle life and increase the high critical current density (CCD) from C/20 to C/2 in comparison with the pure halide and argyrodite electrolytes. Furthermore, compared to the original halide and argyrodite electrolytes, a high initial coulombic efficiency and cycle life can be maintained when combined with a full Li/NCM cell. This approach to improving halide-based SSBs can provide a fairly simple and efficient strategy. Acknowledgements This project has received funding from the European Union's Horizon Europe programme for research and innovation under grant agreement No. 101069681 (HELENA project).

Pinnwall: Heterogeneous Electrode Models from Integrating Machine Learning and Atomistic Simulation

Electrochemical energy storage always involves the capacitive process. The prevailing electrode model used to study such polarizable electrode-electrolyte systems is the Siepmann-Sprik model, which has been recently extended to study the metallicity in the electrode model by including the Thomas-Fermi screening length. Nevertheless, a further extension to heterogeneous electrode models is required. Here, we address this challenge by integrating the atomistic machine learning code (PiNN) [1] for generating the base charge [2] and response kernel [3] and the classical molecular dynamics code (MetalWalls). This leads to the development of the PiNNwall [4] interface. Apart from the cases of chemically doped graphene and graphene oxide electrodes as shown in this study, the PiNNwall interface also allows us to probe polarized oxide surfaces in which both the proton charge and the electronic charge can coexist. Therefore, this work opens the door for modelling heterogeneous and complex electrode materials often found in energy storage systems.[1] Shao, Y.; Hellström, M.; Mitev, P. D.; Knijff, L.; Zhang, C. PiNN: A python library for building atomic neural networks of molecules and materials. J. Chem. Inf. Model. 2020, 60, 1184.[2] Knijff, L.; Zhang, C. Machine learning inference of molecular dipole moment in liquid water. Mach. Learn.: Sci. Technol. 2021, 2, 03LT03.[3] Shao, Y.; Andersson, L.; Knijff, L.; Zhang, C. Finite-field coupling via learning the charge response kernel. Electron. Struct. 2022, 4, 014012.[4] Dufils, T., Knijff, L., Shao, Y. and Zhang, C. PiNNwall: heterogeneous electrode models from integrating machine learning and atomistic simulation. arXiv preprint arXiv:2303.15307. 2023.*This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (Grant Agreement No. 949012). We also acknowledge the support from the Centre for Interdisciplinary Mathematics (CIM) and the AI4Research initiative at Uppsala University.

Understanding the Interplay between Temperature, State of Health, Rate of Ageing, and Overvoltage in Li-Ion Battery Cells

Li-ion batteries are currently the most popular battery technology. However, their service life remains limited and is typically in a range of 2-10 years of active use. The ageing is influenced by the materials used, temperature, charge/discharge rate and architecture of the battery cells. The governing ageing mechanisms are generally related to material stability, with the formation of solid-electrode interphase (SEI), decomposition of active materials or electrolyte and loss of contact being the main contributors. Externally, this can be observed as loss of capacity, increase in internal resistance (overvoltage or polarization) and heating of the cell while in use.In this work, we demonstrate how Arrhenius plots are a valuable tool to understand the rate of battery cell ageing over its operational temperature range [1,2]. The V-shaped Arrhenius plots correspond to two ageing mechanisms, lithium plating and growth of SEI, with the intersection (crossover) denoting the optimum temperature for the highest service life. The crossover temperature shifts towards higher values with increasing C-rate and anode thickness and depends on the state of health of the battery. The study shows that using Arrhenius-type dependences of the ageing rate can provide valuable insights for quality control and battery management systems, extending the service life of battery cells.Overvoltage of the battery cell typically grows as the battery cell ages. This increased internal resistance leads to a decrease in the battery's ability to deliver current, and thus reduces its power or what is in some cases called ‘rate capability’. We have studied this phenomenon for lab-assembled half-cells with LiFePO4 and NCM 811 cathode as well as for commercial cells, showing the overvoltage as a function of battery cell’s state of health, C-rate and temperature. While ultimately the overvoltage is undesirable, we show how it correlates with battery’s state of health and can be used as an effective predictor of the remaining service life of the battery cell from the operational data without performing a full charge and discharge measurement in a controlled environment. This reduces the failure risk and improves the safety and reliability of the battery. Acknowledgements Authors acknowledge Latvian Council of Science project “Cycle life prediction of lithium-ion battery electrodes and cells, utilizing current-voltage response measurements”, project No. LZP-2020/1-0425. Institute of Solid-State Physics, University of Latvia as the Centre of Excellence has received funding from the European Union's Horizon 2020 Framework Program H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART2. References Bozorgchenani, M., Kucinskis, G., Wohlfahrt-Mehrens, M. & Waldmann, T. Experimental Confirmation of C-Rate Dependent Minima Shifts in Arrhenius Plots of Li-Ion Battery Aging. J. Electrochem. Soc. 169, 030509 (2022).Kucinskis, G. et al. Arrhenius plots for Li-ion battery ageing as a function of temperature, C-rate, and ageing state – An experimental study. J. Power Sources 549, 232129 (2022).

Adsorption of 2-Mercaptobenzothiazole Organic Inhibitor and Its Effects on Copper Anodic Oxidation in Alkaline Environment

2-Mercaptobenzothiazole (2-MBT) is well established as an effective organic corrosion inhibitor for the protection of copper and other metals. The presence of heteroatoms (2 sulphur and 1 nitrogen) in its structure, enables it to bond to the metallic substrate and form a protective barrier layer on the surface which restricts the pathways for the corrosive ions to the metal surface. However, despite numerous works discussing the inhibiting properties on copper, several questions remain, notably regarding the role played by the surface native oxide on the bonding mechanisms, the stability, and the inhibition efficiency of the organic film formed in various environments.In this work, the adsorption of 2-MBT on copper and its effects on anodic oxide growth in a strong alkaline medium (0.1 M NaOH solution) were investigated. Various cathodic pre-treatment methods were applied to modify and control the native oxide-covered Cu surface during the formation of the inhibitor layer. Cyclic voltammetry (CV) tests were performed to determine how the growth of anodic Cu(I) oxide is altered by the 2-MBT organic inhibitor layers pre-adsorbed in different pre-treatment conditions. Additionally, X-ray photoelectron spectroscopy (XPS) and time-of-flight – secondary ion mass spectrometry (ToF-SIMS) were used to investigate the bonding mechanisms of the 2-MBT molecule to the copper surface, including the role of surface native oxides in the formation of the interface with the inhibitor, the effect of increased exposure time to the inhibitor, the stability of the organic inhibitor layer upon anodic polarisation, and the oxide growth upon anodic polarization. The absence of chlorides eliminates their interference in the understanding the oxidation process in a 2-MBT-containing alkaline solution. Additionally, anodic oxidation is studied in the Cu(I) potential range, which allows us to evaluate the effects of 2-MBT on the oxide layer that forms directly on the bare metallic substrate.The results show that 2-MBT significantly impedes the growth of the passivating Cu(I) oxide by forming a multilayered organic film with the inner layer chemisorbed to the surface. A major factor influencing the formation and properties of the organic barrier layer is the presence and structure of the interfacial native oxides on which it forms. The 2-MBT molecules bond to the copper substrate mostly via its sulphur atoms along with a small fraction of the nitrogen atoms also bonding to the metallic substrate. Additionally, there is an interaction between the inhibitor molecules and copper released from the surface to form metal-organic complexes in the outer layers of the thicker films. Longer exposure times to the inhibitor of a surface with negligible oxides increased the efficiency of the organic barrier layer in impeding the growth of anodic oxide.Upon anodic polarisation, the 2-MBT barrier layer grows in thickness, with inclusion of Cu-2-MBT complexes. It is proposed that the thiolate form of 2-MBT, which is the dominant conformer in an alkaline environment, allows for additional bonding possibilities to the Cu atoms and Cu(I) ions of or released from the surface oxide, forming Cu-2-MBT complexes that deposit on the surface and thus increasing the thickness of the organic barrier layer. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Advanced grant agreement No. 741123, CIMNAS).

Promoting AEM Water Electrolyzer Performance and Reproducibility by Tumbler Milling of Ni3fe-LDH OER Catalyst

Anion exchange membrane water electrolysis is an attractive clean energy technology for producing hydrogen for energy storage, transport 1,2 and numerous other applications. Rational choice of highly active and stable catalysts as well as the proper design of catalyst layers are crucial to achieve technical relevance of electrolyser systems. The establishment of clear understanding of optimal catalyst treatment and methods of implementation are key steps towards optimized electrolyzer performance and durability. One aspect of catalyst performance in catalyst layers is the catalyst size distribution. A multimodal size distribution of catalyst particles or agglomerates can jeopardize the layer homogeneity and thus electrode performance.In this work, the effect of high-energy ball tumbling milling on the promising Ni3Fe-LDH OER catalyst followed by catalyst dispersion control was correlated to the microstructure of the catalyst layer, the achieved catalyst activity and utilization, and the resulting single cell performance and stability. Physico-chemical characterization confirmed the stable layered double hydroxide structure of the catalyst. By milling, a 300-fold reduction of catalyst agglomerate size, and an 8.8-fold increase of the geometrical surface was achieved. The optimized solvent compositions effectively increased the catalyst ink stability. We found that a significantly decreased catalyst agglomerate size resulted in very homogeneous mixtures of catalyst and ionomer. By tailoring the electrode structure design, lower internal electronic resistances of the electrodes, decreased charge-transfer resistances (Rct) of the membrane electrode assembly, and stable single cell durability of 1000 h with a minor degradation rate of 57 µV h-1 were accomplished.This work presents a facile and scalable approach of NiFe-LDH catalyst treatment and dispersion control and provides a guideline to follow for further electrode development and increased AEM water electrolyzer performances. References (1) Hydrogen Applications. Hydrogen Europe. 2020. https://hydrogeneurope.eu/hydrogen-applications (accessed Jan 7, 2022).(2) Vincent, I.; Bessarabov, D. Low Cost Hydrogen Production by Anion Exchange Membrane Electrolysis: A Review. Renew. Sustain. Energy Rev. 2018, 81 (August 2016), 1690–1704. https://doi.org/10.1016/j.rser.2017.05.258. This work has been performed in the frame of the CHANNEL project. This project has received funding from the Fuel Cells and Hydrogen 2 Joint Undertaking (now Clean Hydrogen Partnership) under grant agreement No 875088. This Joint undertaking receives support from the European Union's Horizon 2020 Research and Innovation program, Hydrogen Europe and Hydrogen Europe Research.

Understanding the Connection between Li-Ion Transport Number and Electrochemical Performance in Fluorinated Ether-Based Electrolytes

As high-performance batteries increase in demand, lithium metal batteries (LMBs) have attracted increasing attention in recent years. Nonetheless, LMBs are limited in their performance due to a low cation transport number (tLi+) of non-aqueous liquid electrolytes, which is the ratio of charge transport of Li-ions to its counterion. This study investigated fluorinated ether-based electrolytes (1,2-(1,1,2,2-tetra fluoroethoxy) ethane, TFEE) with 1,2-dioxolane (DOL) as a co-solvent that were found to have tLi+ of 0.70, which was determined through electrochemical impedance spectroscopy, EIS. This electrolyte mixture gives a low electrolyte coulombic efficiency and poor stability tested in both Li-Cu half and Li – Li4Ti5O12 full cells. The same fluorinated electrolyte with dimethoxy ethane (DME) as a co-solvent showed better coulombic efficiency and stability despite its low tLi+ of 0.18. A significant migration resistance through the porous solid electrolyte interface (SEI) in the case of TFEE-DOL electrolytes is suspected to explain the observed discrepancy, as demonstrated by EIS and X-ray photoelectron spectroscopy. We propose that the properties/process of the Li anode are more crucial for LMBs’ performance than the ionic transport through the bulk electrolyte. Furthermore, the transport number should be determined carefully to avoid any spurious effects associated with SEI properties. Acknowledgments This work has received funding from the European Union Horizon 2020 research and innovation DESTINY program under grant agreement No. 945357. Co-financing from Slovenian Research Agency (ARRS) is fully acknowledged.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

Role of Allogeneic Stem Cell Transplantation in Preventing Relapse in Adult BCR::ABL1-like Acute Lymphoblastic Leukemia

Background Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by the activation of several kinase pathways that promote treatment resistance leading to poor survival of patients at all ages. Despite the use of tyrosine kinase inhibitors in the Ph-like ABL-class subtype (15% Ph-like ALL), there is not a consensus approach for treatment of most patients (JAK-class especially), and the role of allogeneic stem cell transplantation (alloSCT) has scarcely been explored so far (i.e., mandatory vs. MRD-oriented). Objective To assess the outcome of Ph-like patients enrolled in the ongoing ALL19 trial from the Programa Español de Tratamientos en Hematología (PETHEMA) for adults (18-60y) with Ph-negative ALL, and to evaluate the effectiveness of alloSCT in first complete remission (CR). Methods In the ALL19 trial, patients are allocated to alloSCT according both to the end of induction (EOI) measurable residual disease (MRD) level and to high-risk genetic markers such as low-hypodiploidy, KMT2A rearrangement, TP53 biallelic alteration and concomitant deletion of IKZF1 and CDKN2A/B. Therefore, BCR::ABL1-like subtype was not a criteria for early transplantation unless meeting either poor MRD clearance at EOI or concomitant deletion of IKZF1+CDKN2A/B. Patients with MRD≥0.01% on day+35 (EOI) and/or high-risk genetics were assigned to early alloSCT (preceded by 1 cycle of consolidation chemotherapy) while those with good MRD clearance and standard risk genetics received early and delayed consolidation (3 cycles each) and maintenance therapy. Bone marrow or peripheral blood samples were analyzed by G-banding+FISH, SNP array (750K Affymetrix, Thermo Fisher) and next generation sequencing (NGS, with a custom DNA gene panel, Illumina) at diagnosis in 4 reference laboratories. MRD was centrally assessed by next generation flow cytometry with a sensitivity up to 2x10 -6. Results Twenty-four Ph-like out of 248 adult BCP ALL (10%) were detected. Baseline characteristics were similar between Ph-like and the remaining BCP-ALL. Most Ph-like ALL patients showed the JAK-class profile (20/24 [83%]: 17/24 CRLF2 rearrangement[r], 1/24 JAK2r, 1 BLNK::DNTT and 1 JAK2 R683 mutation), 3/24 belonged to the ABL-class subtype (2 ABL2r, 1 NUP214::ABL1) and 1 patient was identified by RNAseq (gene expression profiling similar to BCR::ABL1 ALL) without identifying any rearrangement. Regarding secondary genetic alterations, 17/24 (71%) patients showed the IKZF1 plus profile, 10/23 (43%) harbored JAK2 R683 mutation, 4/23 N/KRAS mutations, 2/23 CRLF2 mutation and 1/23 showed mutations in several genes such as IKZF1, NR3C1 or FLT3, among others. There were no significant differences in the probability of achieving CR between Ph-like and the remaining BCP ALL (15/20 [75%] vs. 137/162 [85%], p=0.334). However, EOI MRD level of Ph-like individuals was significantly poorer (MRD&amp;lt;0.01% Ph-like 4/15 [27%] vs. other BCP-ALL 85/136 [63%], p=0.007). By intention to treat, most Ph-like patients (17/19, 89%) were allocated to alloSCT (vs. 91/153 [59%] in the other BCP-ALL, p=0.011) due to either EOI MRD≥0.01% (9/18), IKZF1+CDKN2A/B concomitant deletions (3/18) or both (6/18). The 2-y overall survival (OS) in both groups was not significantly different (57% [95% CI, 27%-78%] vs. 67% [55%-77%, p=0.304]) (Figure 1). Interestingly, most Ph-like patients died due to treatment-related toxicity (2 transplant-related mortality, 1 CART-related, 1 during induction, 1 in CR and 1 by COVID-19 infection). The 2-y cumulative incidence of relapse (CIR) was also similar (Ph-like 27% [8%-50%] vs. other BCP-ALL 35% [25%-45%], p=0.946) (Figure 1). Conclusions Despite the short follow up of this series, our results show that Ph-like ALL patients have poorer EOI MRD clearance and higher rate of alloSCT realization than the remaining BCP ALL patients, without significant differences in outcome. This suggests that early alloSCT in first CR might overcome the poor prognosis of Ph-like ALL patients. Funding Funded in part by: PI10/01417 y FIS PI19/01183 Ministerio de Salud Carlos III, JCyL_SA118P20, FMM21/002_AP176752021, “La Caixa” Foundation, Pfizer Spain, Fundación PETHEMA. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No IMI001-07. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Distinct Role of STAT3 and STAT5 Factors in MDS and AML

Introduction: Myelodysplastic Syndrome (MDS) refers to a heterogeneous group of clonal hematologic disorders characterized by hematopoietic dysfunctions and impaired differentiation in the hematopoietic stem and progenitor cells compartment. MDS is commonly referred to as a pre-leukemic stage due to the increased risk of progression to Acute Myeloid Leukemia (AML). AML is an aggressive hematologic malignancy characterized by the accumulation of immature myeloblasts in the bone marrow and the peripheral blood. Signal transducers and activators of transcription 3 and 5 (STAT3 and STAT5) are important regulators of several cellular processes including cell proliferation and survival. Abnormal STAT3 and STAT5 signaling has been implicated in various solid and hematologic malignancies, including MDS and AML, which renders them appealing targets for the development of novel therapeutic strategies. Materials: STAT3, STAT5A or STAT5B knock-downs have been generated in two AML (MOLM-13 and Kasumi-1) and two MDS (MDS92 and MDS-L, gift of Prof. Kaoru Tohyama) cell lines, using shRNAs through lenti-viral delivery. The 4 biological replicates with the highest levels of knock-downs for STAT5A, STAT5B or STAT3 have been selected for each cell line and mRNA sequencing has been performed. To define the genome-wide binding of STAT5A, STAT5B and STAT3 in the two conditions, CUT&amp;Tag has been performed in wild type MOLM-13, Kasumi-1 and MDS-L cells. Additionally, ATAC sequencing has been carried out in the same cell lines to investigate the chromatin conformation changes between the two conditions. Furthermore, STAT3, STAT5A and STAT5B knock-downs have been conducted using shRNAs through lenti-viral delivery in CD34+ enriched cells, isolated from bone marrow mononuclear cells of 14 high-risk MDS patients and 14 secondary (MDS-related) AML patients. The samples have been processed for mRNA-Sequencing to model the leukemic transformation in primary human cells. Results: To elucidate the role of STAT3 and STAT5 in MDS to AML transformation, changes in STAT3 and STAT5 target gene networks have been identified. mRNA sequencing data from STAT3, STAT5A or STAT5B knock-downs in MDS and AML cell lines revealed a distinct role of the three factors in each state. The differential binding of each factor, explored through CUT&amp;Tag, and the gene expression profiles in MDS and AML reciprocally reveal a different function of each factor, including pathways involved in cell cycle and apoptosis. Also, the direct and indirect target genes of STAT3, STAT5A and STAT5B in each condition, as well as a possible interplay between STAT3 and STAT5 activation in AML has been uncovered. The exploration of the chromatin accessibility landscapes between the MDS and AML conditions through ATAC sequencing has provided an insight into the chromatin conformation states, unveiling potential leukemia promoting networks, as well as the involvement of STAT3 and STAT5 pathways in the malignant transformation. Furthermore, a potential cross talk of STAT3 and STAT5 factors with the IKAROS family members, has been linked to AML transformation, as significant differential regulation has been detected between MDS and AML conditions after knock-down of STAT5A and STAT5B. The results are currently validated in primary hematopoietic cells of MDS and AML patients after STAT3, STAT5A or STAT5B knock-downs. Conclusions: Our results show a different role between the two STAT5 factors (STAT5A and STAT5B) in MDS and AML conditions and delineate the role of STAT5A, STAT5B and STAT3 factors and their target gene networks in leukemic transformation, thus providing novel targets for therapeutic management of MSD and AML. Funding: This project is funded by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813091 (ARCH)

ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases

Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice. We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available. 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex. Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use. European Union Horizon 2020 Research and Innovation Programme.

A systematic review of the evidence supporting the use of surgical aortic and mitral valves: an update from the CORE MD consortium

Abstract Introduction The European Union (EU) Medical Device Regulation (MDR) 2017/745 challenges the medical community to engage with regulators, notified bodies and industry to develop transparent, rigorous and proportionate methods to evaluate the clinical safety and efficacy of medical devices and to monitor their performance. As part of the EU Horizon 2020 funded CORE-MD project, we performed a systematic review of the published scientific evidence available for surgical heart valve replacements for native aortic and mitral valve pathologies. Purpose The aim of this analysis is to review the scientific evidence available which supports the use of currently available surgical aortic and mitral valves. Methods A systematic literature review was conducted using Ovid, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL). We included only surgical aortic and mitral valves that received CE Mark approval from the year 2000 onwards. We included any study of prospective design (randomised or non-randomised clinical trials of any design) in humans, published between 2000 and 2021. We excluded retrospective studies, case reports, reviews, systematic reviews, meta-analyses, and expert opinion documents. Title and abstract screening, full-text review, risk of bias evaluation and data collection were performed by two authors independently, with disagreements resolved by discussion with a third author. Results A total of 17 surgical aortic valves and 4 surgical mitral valves were identified based on the CE mark criterion (Figure 1). The initial literature search identified 4901 and 3696 potentially eligible papers in the aortic and mitral valve categories, respectively. Finally, 39 aortic and 3 mitral valve studies were included (Figure 2). The majority of included studies (90%) had a non-randomised, prospective, observational design, with 68% receiving industry funding. The median number of patients included was 295 [interquartile range (IQR): 153, 689] with a median maximum follow up of 24 months [IQR: 12, 60]. Only 50% of the identified studies had a pre-specified registered study protocol and only 5% included a power calculation to estimate the required study size. No study reported patient involvement in the study design and only 15% of studies had a comparator group. Using the ROBINS I AND II assessment tools, 90% of the included studies were classified as having a high or serious risk of bias. Conclusion The evidence available for currently used surgical aortic and mitral replacement heart valves is largely from small, industry funded, non-randomised controlled trials. The median duration of maximum follow up was only 24 months, the majority of studies were classed as having a high/serious risk of bias and only half had a pre-registered study protocol. These results highlight the limitations of the available scientific evidence supporting the surgical aortic and mitral valves used in current clinical practice.Surgical aortic and mitral valvesSummary of literature search results

Performance of the WID-qEC test versus sonography to detect uterine cancers in women with abnormal uterine bleeding (EPI-SURE): a prospective, consecutive observational cohort study in the UK

To detect uterine cancer, simpler and more specific index tests are needed to triage women with abnormal uterine bleeding to a reference histology test. We aimed to compare the performance of conventional index imaging tests with the novel WID-qEC DNA methylation test in terms of detecting the presence or absence of uterine cancers in women with abnormal uterine bleeding. EPI-SURE was a prospective, observational study that invited all women aged 45 years and older with abnormal uterine bleeding attending a tertiary gynaecological diagnostic referral centre at University College London Hospital (London, UK) to participate. Women meeting these inclusion criteria who consented to participate were included. Pregnant women and those with previous hysterectomy were excluded. A cervicovaginal sample for the WID-qEC test was obtained before standard assessment using index imaging tests (ie, ultrasound) and, where applicable, reference histology (ie, biopsy, hysteroscopy, or both) was performed. Technicians performing the WID-qEC test were masked to the final clinical outcome. The result of the WID-qEC test is defined as the sum of the percentage of fully methylated reference (ΣPMR) of the ZSCAN12 and GYPC regions. Patients were followed until diagnostic resolution or until June 12, 2023. The primary outcome was to assess the real-world performance of the WID-qEC test in comparison with ultrasound with regard to the area under the receiver-operating-characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values. EPI-SURE is registered with ISRCTN (16815568). From June 1, 2022, to Nov 24, 2022, 474 women were deemed eligible to participate. 74 did not accept the invitation to participate, and one woman withdrew after providing consent. 399 women were included in the primary analysis cohort. Based on 603 index imaging tests, 186 (47%) women were recommended for a reference histology test (ie, biopsy, hysteroscopy, or both). 12 women were diagnosed with cancer, 375 were not diagnosed with cancer, and 12 had inconclusive clinical outcomes and were considered study dropouts. 198 reference histology test procedures detected nine cases of cancer and missed two; one further cancer was directly diagnosed at hysterectomy without a previous reference test. The AUC for detection of uterine cancer based on endometrial thickness in mm was 87·2% (95% CI 71·1-100·0) versus 94·3% (84·7-100·0) based on WID-qEC (p=0·48). Endometrial thickness assessment on ultrasound scan was possible in 379 (95%) of the 399 women and a prespecified cut-off of 4·5 mm or more showed a sensitivity of 90·9% (95% CI 62·3-98·4), a specificity of 79·1% (74·5-82·9), a positive predictive value of 11·8% (6·5-20·3), and a negative predictive value of 99·6% (98·0-99·9). The WID-qEC test was possible in 390 (98%) of the 399 patients with a sensitivity of 90·9% (95% CI 62·3-98·4), a specificity of 92·1% (88·9-94·4), a positive predictive value of 25·6% (14·6-41·1), and a negative predictive value of 99·7% (98·3-99·9), when the prespecified threshold of 0·03 ΣPMR or more was applied. When a higher threshold (≥0·3 ΣPMR) was applied the specificity increased to 97·3% (95% CI 95·1-98·5) without a change in sensitivity. The WID-qEC test delivers fast results and shows improved performance compared with a combination of imaging index tests. Triage of women with abnormal uterine bleeding using the WID-qEC test could reduce the number of women requiring histological assessments for identification of potential malignancy and specifically reduce the false positive rate. The Eve Appeal, Land Tirol, and the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme.

Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by gonadotropin-releasing hormone (GnRH) neurons might be related to ovarian dysfunction in PCOS, although the link in this disordered brain-to-ovary communication remains unclear. Here, we manipulated GnRH neurons using chemogenetics in adult female mice to unveil whether chronic overaction of these neurons would trigger PCOS-like hormonal and reproductive impairments. We used adult Gnrh1cre female mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in hypophysiotropic GnRH neurons. Chronic chemogenetic activation protocol was carried out with clozapine N-oxide (CNO) i.p. injections every 48h over a month. We evaluated the reproductive and hormonal profile before, during, and two months after chemogenetic manipulations. We discovered that the overactivation of GnRH neurons was sufficient to disrupt reproductive cycles, promote hyperandrogenism, and induce ovarian dysfunction. These PCOS features were detected with a long-lasting neuroendocrine dysfunction through abnormally high luteinizing hormone (LH) pulse secretion. Additionally, the GnRH-R blockade prevented the establishment of long-term neuroendocrine dysfunction and androgen excess in these animals. Taken together, our results show that hyperactivity of hypothalamic GnRH neurons is a major driver of reproductive and hormonal impairments in PCOS and suggest that antagonizing the aberrant GnRH signaling could be an efficient therapeutic venue for the treatment of PCOS. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n◦ 725149).

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation.

Design and Kinematic Modeling of a Soft Continuum Telescopic Arm for the Self-Assembly Mechanism of a Modular Robot.

In recent years, the development of mining robots has grown significantly, offering improved efficiency and safety in hazardous environments. However, there is still room for improvement in adaptability, scalability, and overall performance. The ROBOMINERS project, funded by the European Union's Horizon 2020 Research and Innovation Program, aims to facilitate Europe's access to mineral resources applying disruptive robotic concepts. One such concept is resilience, which can be achieved providing modular mining robots with the ability to reconfigure during operation. To address this challenge, this article presents the development and kinematic modeling of a soft, telescopic, continuum arm integrated into a modular robot. The arm serves as a mechanical interface for coupling different robotic modules or tools following the principle of the car crane. With a fully 3D-printed design, the arm features two sections of variable length that are driven by an innovative actuation method based on soft racks. It provides a 6 degrees of freedom (DoF) motion. The arm kinematic models are obtained by backbone parameterization assuming constant curvature and independent bending between sections for forward kinematics and applying a machine learning-based approach for inverse kinematics. The models are validated through the evaluation of two trajectories, measuring the deviation in each DoF and rack extension. Furthermore, a demonstration of the arm's coupling procedure between two robotic modules and one possible configuration of the robotic system showcases its functionality.